PEP-CMV + Nivolumab for Brain Cancer

(PRiME II Trial)

Not yet recruiting at 3 trial locations

Overseen By Eric M Thompson, M.D.

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Immunosuppressants, Tumor-directed therapy

Disqualifiers: Pregnancy, Active infection, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for children and young adults with certain aggressive brain cancers. It combines a CMV-directed peptide vaccine (PEP-CMV vaccine) and nivolumab, a type of immunotherapy, to determine if they can safely boost the immune system to fight these cancers. The trial seeks participants with newly-diagnosed or recurrent high-grade gliomas, diffuse midline gliomas, medulloblastoma, or ependymoma. It is particularly relevant for those who have completed standard treatments like surgery and radiation but still need more effective options. Participants should have stable health conditions and manageable neurological symptoms. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients should not be on certain immunosuppressive agents or tumor-directed therapies. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that nivolumab, a type of immunotherapy, is generally safe for treating certain brain tumors. One study found that patients with recurrent glioblastoma, a type of brain cancer, tolerated nivolumab well. Another study confirmed that it can reach and affect brain tumors, suggesting it works as intended without major safety issues.

The PEP-CMV vaccine, which targets a virus linked to certain cancers, has also undergone testing. Research indicates that it is well-tolerated, even in patients who have had many previous treatments, meaning patients did not experience severe side effects from the vaccine.

Since this study is in the early stages, it primarily focuses on safety. Early-phase trials like this are essential to ensure the treatment is safe before exploring its effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of PEP-CMV vaccine and nivolumab for brain cancer because this approach targets the immune system in a novel way. Unlike traditional treatments such as surgery, radiation, or chemotherapy, which directly attack tumor cells, this combination therapy aims to enhance the body's immune response against the cancer. The PEP-CMV vaccine stimulates an immune attack specifically against brain tumor cells expressing the CMV antigen, while nivolumab, an immune checkpoint inhibitor, prevents the cancer from evading this immune response. This dual approach has the potential to not only improve the effectiveness of treatment but also provide a more targeted and personalized therapy option for patients with brain cancer.

What evidence suggests that this trial's treatments could be effective for brain cancer?

Research has shown that the PEP-CMV vaccine, which participants in this trial will receive, may help treat brain tumors by targeting specific proteins linked to the CMV virus. In earlier studies, patients lived without disease progression for an average of 2.5 months, and their overall survival was about 6.4 months. Nivolumab, another treatment in this trial, demonstrated lasting positive effects and longer survival in children with cancer, particularly in those with cancers featuring many genetic changes. Some trials reported partial improvements and better outcomes for patients. Both treatments strengthen the immune system to fight cancer more effectively. These findings suggest that using PEP-CMV with nivolumab could be a promising approach to treating serious brain tumors in children and young adults. ^{3 4 6 7 8}

Who Is on the Research Team?

Eric M Thompson, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for children and young adults with new or recurrent high-grade gliomas, diffuse midline gliomas, medulloblastoma, or ependymoma. Participants must meet specific health criteria to ensure safety during the trial.

Inclusion Criteria

My cancer has spread to other parts of my body.

Patients must be able to understand and sign an IRB approved written informed consent document

My bone marrow is functioning well.

Exclusion Criteria

Patients with active unrelated systemic illness

I am currently undergoing treatment specifically for my tumor.

Pregnant or breast-feeding women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive temozolomide and PEP-CMV vaccine during the induction cycle

11 weeks

Multiple visits for drug administration and monitoring

Maintenance Treatment

Participants continue to receive PEP-CMV vaccine every 28 days until recurrence or progression

Until progression

Monthly visits for vaccine administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 years

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• PEP-CMV vaccine

Trial Overview The study tests a CMV-directed peptide vaccine (PEP-CMV) combined with Nivolumab, an immune checkpoint inhibitor. It also includes Temozolomide chemotherapy and a Tetanus booster to enhance the immune response.

How Is the Trial Designed?

Group I: Phase II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Experimental Treatment 4 Interventions

Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.

Group II: Phase I Stratum III: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Experimental Treatment 4 Interventions

Patients with recurrent/progressive MB or EPN with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.

Group III: Phase I Stratum II: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Experimental Treatment 4 Interventions

Patients with recurrent/progressive HGG or DMG with measurable disease can be enrolled at any point following recurrence regardless of any prior therapy. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.

Group IV: Phase I Stratum I: Temozolomide + Nivolumab + PEP-CMV vaccine + Td booster Experimental Treatment 4 Interventions

Patients with newly-diagnosed high-grade glioma or DMG may be enrolled any time within 42 days after completing radiation. Cycle 1 (Induction cycle) is 77±2 days. Will receive 1 course of temozolomide 200 mg/m\^2/day x 5 days on Days 1-5 of cycle 1 \& receive PEP-CMV vaccine at dose level 1 (250 μg/m\^2) on Days 21, 35 ±2 days, and 49 ±2 days. After the induction cycle, each subsequent cycle is 28 days. Starting in cycle 2, PEP-CMV vaccine is administered every 28 days on day 1 of each course. Patient can continue to receive PEP-CMV every 28 days until recurrence/progression. Patients will receive a tetanus (Td) booster at the time of enrollment. Immunotherapy begins with a Td pre-conditioning vaccine delivered 6-24 hours prior to the first vaccine on day 21. Patients will also receive nivolumab 3 mg/kg IV on day 14±1 day then every 14 days ±2 days thereafter.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The novel PeptiENV cancer vaccine, which incorporates the MMR vaccine, significantly enhances both local and systemic immune responses against tumors when administered directly into the tumor.

Combining PeptiENV therapy with immune checkpoint inhibitors not only improves tumor control and survival rates in mice but also increases the effectiveness of the checkpoint inhibitors, showing that prior immunity to the MMR vaccine does not hinder the cancer treatment's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel cancer vaccine for melanoma based on an approved vaccine against measles, mumps, and rubella. Fusciello, M., Ylösmäki, E., Feola, S., et al.[2022]

DCVax-Brain, a personalized treatment using dendritic cells to target brain tumors, shows promise in inducing antitumor immunity with low toxicity in patients with glioblastoma multiforme (GBM).

Recent trials indicate that DC vaccine therapy correlates with clinical improvements in GBM patients, although some reports suggest possible selection bias in the findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DCVax-Brain and DC vaccines in the treatment of GBM. Wheeler, CJ., Black, KL.[2019]

In a Phase II study involving 18 patients with leptomeningeal disease, the combination of ipilimumab and nivolumab showed promising efficacy, with 44% of patients alive at three months, surpassing the expected 18%.

The treatment had an acceptable safety profile, although one-third of patients experienced significant adverse events, including two cases leading to treatment discontinuation due to hepatitis and colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. Brastianos, PK., Strickland, MR., Lee, EQ., et al.[2021]

In a study of 119 patients with melanoma brain metastases, those who were asymptomatic showed a significant clinical benefit from the combination of nivolumab and ipilimumab, with a 36-month overall survival rate of 71.9%.

Symptomatic patients had much lower efficacy, with only 36.6% overall survival at 36 months, highlighting the challenges in treating symptomatic melanoma brain metastases with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Tawbi, HA., Forsyth, PA., Hodi, FS., et al.[2022]

Human cytomegalovirus (CMV) is found in glioblastoma (GBM) tumors but not in normal brain tissue, suggesting that CMV antigens could be effective targets for immunotherapy.

Research shows that T cells specific to the CMV pp65 antigen can recognize and kill GBM tumor cells derived from patients, supporting the potential for CMV-targeted immunotherapies in treating GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunological targeting of cytomegalovirus for glioblastoma therapy. Nair, SK., Sampson, JH., Mitchell, DA.[2021]

Certain high-risk groups, such as HIV-infected individuals, transplant patients, and newborns, are particularly vulnerable to diseases caused by human cytomegalovirus (CMV), highlighting the need for effective vaccination strategies.

While there are currently no licensed CMV vaccines for humans, various vaccine approaches, including protein subunit, DNA, and live attenuated vaccines, are being tested in clinical trials, showing promise in inducing protective immune responses against CMV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress toward an elusive goal: current status of cytomegalovirus vaccines. Schleiss, MR., Heineman, TC.[2007]

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